08 October 2009

Scientists discover clues to what makes human muscle age

Working
in collaboration with Dr. Michael Kjaer and his research group at the
Institute of Sports Medicine and Centre of Healthy Aging at the
University of Copenhagen in Denmark, the UC Berkeley researchers
compared samples of muscle tissue from nearly 30 healthy men who
participated in an exercise physiology study. The young subjects ranged
from age 21 to 24 and averaged 22.6 years of age, while the old study
participants averaged 71.3 years, with a span of 68 to 74 years of age.

In
experiments conducted by Dr. Charlotte Suetta, a post-doctoral
researcher in Kjaer's lab, muscle biopsies were taken from the
quadriceps of all the subjects at the beginning of the study. The men
then had the leg from which the muscle tissue was taken immobilized in
a cast for two weeks to simulate muscle atrophy. After the cast was
removed, the study participants exercised with weights to regain muscle
mass in their newly freed legs. Additional samples of muscle tissue for
each subject were taken at three days and again at four weeks after
cast removal, and then sent to UC Berkeley for analysis.

Morgan
Carlson and Michael Conboy, researchers at UC Berkeley, found that
before the legs were immobilized, the adult stem cells responsible for
muscle repair and regeneration were only half as numerous in the old
muscle as they were in young tissue. That difference increased even
more during the exercise phase, with younger tissue having four times
more regenerative cells that were actively repairing worn tissue
compared with the old muscle, in which muscle stem cells remained
inactive. The researchers also observed that old muscle showed signs of
inflammatory response and scar formation during immobility and again
four weeks after the cast was removed.

"Two weeks of
immobilization only mildly affected young muscle, in terms of tissue
maintenance and functionality, whereas old muscle began to atrophy and
manifest signs of rapid tissue deterioration," said Carlson, the
study's first author and a UC Berkeley post-doctoral scholar funded in
part by CIRM. "The old muscle also didn't recover as well with
exercise. This emphasizes the importance of older populations staying
active because the evidence is that for their muscle, long periods of
disuse may irrevocably worsen the stem cells' regenerative environment."

At
the same time, the researchers warned that in the elderly, too rigorous
an exercise program after immobility may also cause replacement of
functional muscle by scarring and inflammation. "It's like a Catch-22,"
said Conboy.

The researchers further examined the response of
the human muscle to biochemical signals. They learned from previous
studies that adult muscle stem cells have a receptor called Notch,
which triggers growth when activated. Those stem cells also have a
receptor for the protein TGF-beta that, when excessively activated,
sets off a chain reaction that ultimately inhibits a cell's ability to
divide.

The researchers said that aging in mice is associated in
part with the progressive decline of Notch and increased levels of
TGF-beta, ultimately blocking the stem cells' capacity to effectively
rebuild the body.

This study revealed that the same pathways are
at play in human muscle, but also showed for the first time that
mitogen-activated protein (MAP) kinase was an important positive
regulator of Notch activity essential for human muscle repair, and that
it was rendered inactive in old tissue. MAP kinase (MAPK) is familiar
to developmental biologists since it is an important enzyme for organ
formation in such diverse species as nematodes, fruit flies and mice.

For
old human muscle, MAPK levels are low, so the Notch pathway is not
activated and the stem cells no longer perform their muscle
regeneration jobs properly, the researchers said.

When levels of
MAPK were experimentally inhibited, young human muscle was no longer
able to regenerate. The reverse was true when the researchers cultured
old human muscle in a solution where activation of MAPK had been
forced. In that case, the regenerative ability of the old muscle was
significantly enhanced.

"The fact that this MAPK pathway has
been conserved throughout evolution, from worms to flies to humans,
shows that it is important," said Conboy. "Now we know that it plays a
key role in regulation and aging of human tissue regeneration. In
practical terms, we now know that to enhance regeneration of old human
muscle and restore tissue health, we can either target the MAPK or the
Notch pathways. The ultimate goal, of course, is to move this research
toward clinical trials."